Apoptosis, or programmed cell death, is a naturally occurring process that has been strongly conserved during evolution to prevent uncontrolled cell proliferation. This form of cell suicide plays a crucial role in the development and maintenance of multicellular organisms by eliminating superfluous or unwanted cells. However, if this process goes awry, excessive apoptosis results in cell loss and degenerative disorders, while insufficient apoptosis contributes to the development of cancer, autoimmune disorders and viral infections (Thompson, Science, 1995, 267, 1456-1462).
Although several stimuli can induce apoptosis, little is known about the intermediate signaling events, including inhibition, that connect the apoptotic signal to a common cell death pathway conserved across many species. Recently, a family of apoptosis inhibitor proteins homologous to those produced by viruses has been identified in humans.
Cellular Inhibitor of Apoptosis-1 (also known as c-IAP-1, apoptosis inhibitor 1, API-1, hIAP-2, and MIHB) is a member of the inhibitor of apoptosis (IAP) family of anti-apoptotic proteins which interfere with the transmission of intracellular death signals. It was first cloned and characterized as a component of the TNFR2-TRAF signaling pathway (Rothe et al., Cell, 1994, 78, 681-692) and was shown to be recruited to the cytoplasmic domain of TNFR2 in association with a TRAF2-TRAF1 heterocomplex (Rothe et al., Cell, 1995, 83, 1243-1252). Later it was identified as a factor that could inhibit apoptosis caused by the overexpression of interleukin 1 beta converting enzyme (ICE) or caspase-1, a protease required for apoptosis in mammals (Uren et al., Proc. Natl. Acad. Sci. U S A, 1996, 93, 4974-4978). Subsequently, it has been shown that Cellular Inhibitor of Apoptosis-1 inhibits other cell death proteases, namely caspase-3, caspase-7 and caspase-8 (Deveraux et al., Embo J., 1998, 17, 2215-2223; Roy et al., Embo J., 1997, 16, 6914-6925; Wang et al., Science, 1998, 281, 1680-1683). Furthermore, Cellular Inhibitor of Apoptosis-1 has been shown to play a role in TNFR1 signaling pathways which are independent of the TNFR2 pathways previously identified (Shu et al., Proc. Natl. Acad. Sci. U S A, 1996, 93, 13973-13978).
Cellular Inhibitor of Apoptosis-1 mRNA expression is most abundant in thymus, testis and ovary (Rothe et al., Cell, 1995, 83, 1243-1252) and has been shown to be regulated during follicular development of rat granulosa and theca cells suggesting a role for Cellular Inhibitor of Apoptosis-1 in the control of stage-specific follicular atresia (Li et al., Endocrinology, 1998, 139, 1321-1328).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of Cellular Inhibitor of Apoptosis-1.
To date, strategies aimed at inhibiting Cellular Inhibitor of Apoptosis-1 function have involved the use of molecules that block upstream entities including the TRAF2-TRAF1 heterocomplex and components of the TNF signaling cascade.
However, these strategies are untested as therapeutic protocols as well as being non-specific to Cellular Inhibitor of Apoptosis-1, as many divergent pathways arise from TNF signaling. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting Cellular Inhibitor of Apoptosis-1 function. It is therefore believed that antisense oligonucleotides will provide a promising new pharmaceutical tool for the effective and specific modulation of Cellular Inhibitor of Apoptosis-1 expression.